Despite successful ART that keeps HIV at non-detectable levels in plasma, HIV is not eradicated and when patients are taken off therapy, virus can quickly rebound. In addition, it is recognized that chronic immune activation occurs in patients on successful ART and the CNS effects of this include cognitive dysfunction. The source of the rebounding virus and cells that are activated with chronic infection include monocyte/macrophages. In this competitive renewal application we propose to study: 1) mechanisms that establish and maintain persistence of SIV- DNA in the CNS, 2) monocyte/macrophages that traffic out of the CNS that can be viral infected. We propose to use ART alone and in combination with a new oral form of a polyamine synthesis inhibitor, termed PA300, that targets monocyte/macrophage activation, traffic and infection. We propose to study monocyte/macrophages in blood that traffic to the CNS, macrophage accumulation in the CNS that establishes and maintains reservoirs of proviral DNA, and study the effects of ART and PA300 on this reservoir. Next, the effects of ART and PA300 on the traffic of CD163+ macrophages out of the CNS to peripheral lymph organs will be studied. Successful completion of this application will ascertain monocyte/macrophage subtypes in blood and the CNS that are proviral reservoirs, the effects of ART and PA300 to clear these reservoirs, and their effects on SIV infected cells leaving the CNS. PUBLIC HEALTH RELEVANCE: With effective antiretroviral therapy (ART), there is emerging evidence of chronic system immune activation including lymphocytes and monocyte/macrophages that continues to contribute to AIDS-related pathology and HAND (HIV-associated neurocognitive disorders). In this application, we will use a rhesus macaque SIV- infection model to define monocyte/macrophage reservoirs of SIV-DNA, and to use effective ART alone and with an adjunctive monocyte-directed therapy, to define the establishment, maintenance, and clearance of SIV- DNA in the CNS. Moreover, we propose to define the routes of egress of monocyte/macrophage, and the effect of therapy to eradicate this important HIV reservoir that can potentially reseed the periphery with virus from the CNS, even if there are non-detectable levels of virus in the plasma.